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Amiloride, hydrochlorothiazide and [keywords]
- Effects of aerobic exercise and drug therapy on blood pressure and antihypertensive drugs: a randomized controlled trial. [Journal Article]
- Afr Health Sci 2013 Mar; 13(1):1-9.
Although aerobic exercise has been shown to lower blood pressure (BP) in human beings, its additive BP-reducing effect on antihypertensive drug therapy seems to have been investigated in only laboratory animals.This study investigated the effects of aerobic dance combined with antihypertensive drugs on BP and number of antihypertensive drugs in individuals with hypertension.This open label randomised-controlled trial involved new-diagnosed male and female individuals with mild-to-moderate essential hypertension after at least four weeks of treatment. They were randomly assigned to drug therapy (Normoretic: Hydrochlorothiazide + amiloride hydrochloride, and Amlodipine) (control: n=33) and aerobic dance combined with drug therapy (exercise: n=30) groups. Intervention in each group lasted 12 weeks. BP was measured at baseline and during and pos-intervention. Number of antihypertensive drugs was recorded post-intervention.There were significant reductions in SBP at some periods of the intervention in the exercise group (p=0.000 to 0.002) and control group (p=0.001 to 0.002), and significant difference in DBP at some periods of the intervention in exercise group (p=0.000 to 0.003) and control group (p=0.000 to 0.001). SBP (p=0.066) and DBP (p=0.100) did not differ between the two groups post-12-week intervention. The BP control rates were similar between the exercises (56.7%) and control (35.5%) groups (p=0.075). Similarly, between-group difference in the number of drugs was not significant (p=0.511).This preliminary report demonstrates the tendency of aerobic dance to enhance BP control in individuals on two antihypertensive drugs without BP control.
- Screening of pharmacologic adulterant classes in herbal formulations using voltammetry of microparticles. [Journal Article, Research Support, Non-U.S. Gov't]
- J Pharm Biomed Anal 2013 Feb 23.:194-204.
A solid state electrochemical method for screening different families of adulterant chemicals illegally added to commercial phytotherapuetic formulations is described. The proposed method, based on the voltammetry of microparticles approach, permits a fast and sensitive way to distinguish between anorexics (amfepramone, fenproporex, sibutramine), benzozodiazepinic anxiolytics (clonazepam, flurazepam, alprazolam, midazolam, medazepam, chlordiazepoxide, diazepam), antidepressants (bupropione, fluoxetine, sertraline, paroxetine), diuretics (hydrochlorothiazide, furosemide, chlortalidone, amiloride, spironolactone), and hypoglycemics (glimepiride, chlorpropamide, glibenclamide) based on characteristic voltammetric signals recorded on solid micro- or nanosamples attached to graphite electrodes immersed into aqueous electrolytes.
- Protease stimulation of renal sodium reabsorption in vivo by activation of the collecting duct epithelial sodium channel (ENaC). [Journal Article, Research Support, Non-U.S. Gov't]
- Nephrol Dial Transplant 2013 Apr; 28(4):839-45.
Proteases can increase the activity of the epithelial sodium channel (ENaC) by cleaving its α- or γ-subunit. However, evidence so far comes only from studies in vitro in either heterologous expression systems or isolated nephron segments. The present study has tested whether exposure to a luminal protease can alter sodium reabsorption along the rat collecting duct in vivo.Rats on normal laboratory chow were prepared for renal micropuncture. Late distal tubules of superficial nephrons were microinjected and perfused twice (3 nL min(-1) for 3-6 min) with a solution similar to native tubular fluid, but containing (14)[C]inulin and (22)Na. The first perfusion was either a control solution or solution containing amiloride 1 mM or hydrochlorothiazide (HCTZ ) 1 mM; the second perfusion was either a control solution (time control) or a solution containing chymotrypsin 2 µg mL(-1) ± aprotinin 100 µg mL(-1) or amiloride 1 mM or HCTZ 1 mM. Urinary recoveries of (14)[C]inulin and (22)Na were recorded.In time controls, the Na/In ratio did not change significantly (32.2 ± 3.4% versus 34.5 ± 3.1%). In contrast, chymotrypsin reduced the ratio from 33.3 ± 3.8% to 25.5 ± 2.5% (P < 0.05), indicating an increase in sodium reabsorption. When co-injected with chymotrypsin, the protease inhibitor aprotinin abolished the stimulatory effect of chymotrypsin on sodium reabsorption (31.7 ± 3.4% versus 32.1 ± 2.1%), while aprotinin alone had no effect. When chymotrypsin was co-injected with HCTZ, the Na/In ratio decreased from 36.8 ± 2.3% to 28.0 ± 3.4% (P < 0.05), whereas when given with amiloride, there was no change in the ratio (45.8 ± 3.4% versus 45.5 ± 2.3%), indicating that stimulation of sodium reabsorption by chymotrypsin was ENaC-dependent.These findings demonstrate proteolytic activation of ENaC in vivo, and suggest that changes in protease activity of the glomerular filtrate and tubular fluid in health or disease could affect net renal sodium excretion.
- Feedback inhibition of ENaC during acute sodium loading in vivo. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Am J Physiol Renal Physiol 2013 Jan 15; 304(2):F222-32.
The epithelial Na(+) channel (ENaC) is tightly regulated by sodium intake to maintain whole body sodium homeostasis. In addition, ENaC is inhibited by high levels of intracellular Na(+) [Na(+)](i), presumably to prevent cell Na(+) overload and swelling. However, it is not clear if this regulation is relevant in vivo. We show here that in rats, an acute (4 h) oral sodium load decreases whole-cell amiloride-sensitive currents (I(Na)) in the cortical collecting duct (CCD) even when plasma aldosterone levels are maintained high by infusing the hormone. This was accompanied by decreases in whole-kidney cleaved α-ENaC (2.6 fold), total β-ENaC (1.7 fold), and cleaved γ-ENaC (6.2 fold). In addition, cell-surface β- and γ-ENaC expression was measured using in situ biotinylation. There was a decrease in cell-surface core-glycosylated (2.2 fold) and maturely glycosylated (4.9 fold) β-ENaC and cleaved γ-ENaC (4.7 fold). There were no significant changes for other apical sodium transporters. To investigate the role of increases in Na(+) entry and presumably [Na(+)](i) on ENaC, animals were infused with amiloride prior to and during sodium loading. Blocking Na(+) entry did not inhibit the effect of resalting on I(Na). However, amiloride did prevent decreases in ENaC expression, an effect that was not mimicked by hydrochlorothiazide administration. Na(+) entry and presumably [Na(+)](i) can regulate ENaC expression but does not fully account for the aldosterone-independent decrease in I(Na) during an acute sodium load.
- Effects of the association of potassium citrate and agropyrum repens in renal stone treatment: results of a prospective randomized comparison with potassium citrate. [Comparative Study, Journal Article, Randomized Controlled Trial]
- Arch Ital Urol Androl 2012 Jun; 84(2):61-7.
To evaluate by a prospective randomized controlled study the efficacy of the association of potassium citrate and dry extract of couch grass (Agropyrum repens) (CalcoMEV) in renal stone treatment.50 patients with nephrolithiasis associated with one or more active metabolic alterations that constitute an indication to the use of potassium citrate were randomly divided in two equal unblinded treatment groups. A group of patients was assigned to treatment with the association of potassium citrate and couch grass (at the dose of 24 mEq of potassium citrate and 100 mg of dry extract of Agropyrum repens bis in die) and the other group to potassium citrate (at a dose of 20 mEq ter in die). Each form of main treatment was associated, depending on the results of metabolic basal assessment, to allopurinol and/or an association of amiloride and hydrochlorothiazide and/or pyridoxine. Patients of both groups were advised the same diet based on a reduced intake of sodium, foods rich in oxalate and protein of animal origin, a normalized intake of calcium and an increase in fluid intake (> 2 liters every day).At the end of the 5-month follow-up period, the group treated with the association of potassium citrate and couch grass showed a significant reduction in the total number of stones (-1.0 +/- 0.2 vs. 0.0 +/- 0.2 stones) and in the larger diameter of the stones (-3.6 +/- 0.9 mm vs. 0.0 +/- 0.8 mm), as well as a statistically significant reduction of uric acid urinary excretion (-164.7 +/- 45.3 vs -38 +/- 42 mg/24 h). No significant differences in the two groups were observed with respect to urinary citrate, oxalate and calcium urinary excretions and urinary pH.This prospective randomized study demonstrates the superiority of the association of potassium citrate and dry extract of couch grass, in combination with standard pharmacological and dietary treatment, in reducing the number and size of urinary stones with respect to potassium citrate in association with the same pharmacological and dietary regimen.
- A new application of continuous wavelet transform to overlapping chromatograms for the quantitative analysis of amiloride hydrochloride and hydrochlorothiazide in tablets by ultra-performance liquid chromatography. [Journal Article, Research Support, Non-U.S. Gov't]
- J AOAC Int 2012 May-Jun; 95(3):751-6.
A new application of continuous wavelet transform (CWT) to overlapping peaks in a chromatogram was developed for the quantitative analysis of amiloride hydrochloride (AML) and hydrochlorothiazide (HCT) in tablets. Chromatographic analysis was done by using an ACQUITY ultra-performance LC (UPLC) BEH C18 column (50 x 2.1 mm id, 1.7 pm particle size) and a mobile phase consisting of methanol-0.1 M acetic acid (21 + 79, v/v) at a constant flow rate of 0.3 mL/min with diode array detection at 274 nm. The overlapping chromatographic peaks of the calibration set consisting of AML and HCT mixtures were recorded rapidly by using an ACQUITY UPLC H-Class system. The overlapping UPLC data vectors of AML and HCT drugs and their samples were processed by CWT signal processing methods. The calibration graphs for AML and HCT were computed from the relationship between concentration and areas of chromatographic CWT peaks. The applicability and validity of the improved UPLC-CWT approaches were confirmed by recovery studies and the standard addition technique. The proposed UPLC-CWT methods were applied to the determination of AML and HCT in tablets. The experimental results indicated that the suggested UPLC-CWT signal processing provides accurate and precise results for industrial QC and quantitative evaluation of AML-HCT tablets.
- A 48-week study of amlodipine plus amiloride / hydrochlorothiazide vs. amlodipine plus telmisartan in the treatment of hypertension. [JOURNAL ARTICLE]
- Int J Clin Pract 2012 Aug; 66(8):792-799.
Background:Chinese Hypertension Intervention Efficacy (CHIEF) study is a large-scale randomised clinical trial across China, which compares the efficacy of two combination regimens in reducing cardiovascular events associated with hypertension.
Methods:We reported the 48-week efficacy and tolerability of the two antihypertensive regimens in participants from Shandong Province, China. Eligible patients aged 50-79 years were randomised to receive amlodipine plus amiloride/hydrochlorothiazide (Group A) or amlodipine plus telmisartan (Group B). The doses of both regimens were titrated and other antihypertensive agents were added subsequently to achieve a blood pressure (BP) goal (<140/90 mmHg for general population, <130/80 mmHg for diabetics and <150/90 mmHg for elderly). Efficacy variables included the changes of BP, control rates (the proportion of patients achieving a BP goal), and response rates (the proportion of patients achieving a BP goal or a reduction of BP ≥20/10 mmHg). Safety was assessed by monitoring the incidence of adverse events (AEs).
Results:Of the 349 patients enrolled, 314 were randomised and 291 completed the study (141 in Group A and 150 in Group B). At week 48, the BP was reduced by 28.77/15.55 mmHg in Group A and by 31.38/16.07 mmHg in Group B (p > 0.05 for comparisons between Group A and Group B). The control rates (71.79% vs. 77.22%; p = 0.270) and response rates (79.49% vs. 84.81%; p = 0.218) were also similar. For both regimens, the control rates in diabetic patients were relatively lower (31.91% and 32.50%), while those in elderly patients were pretty higher (90.74% and 97.62%). AEs were mild to moderate in severity (17.95% vs. 12.66%, p = 0.193).
Conclusion:Both combination regimens, amlodipine plus amiloride/hydrochlorothiazide and amlodipine plus telmisartan, were effective and safe for the high-risk hypertensive patients.
- Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. [Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- J Hypertens 2012 Aug; 30(8):1656-64.
To compare two drug regimens to treat resistant hypertension.In a prospective, randomized, open blinded endpoint study, 167 patients with mean baseline daytime ambulatory blood pressure 135 mmHg or more and/or 85 mmHg or more, despite 4 weeks' treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day and amlodipine 5 mg/day, were randomized to sequential nephron blockade (group 1, n = 85) or sequential renin-angiotensin system blockade (group 2, n = 82). First, spironolactone 25 mg/day in group 1 or ramipril 5 mg/day in group 2 were added for 4 weeks. Treatment was increased at weeks 4, 8 or 10 if home blood pressure was 135 mmHg or more and/or 85 mmHg or more by sequentially administering furosemide 20 mg/day, furosemide 40 mg/day and amiloride 5 mg/day in group 1, or ramipril 10 mg/day, bisoprolol 5 mg/day and bisoprolol 10 mg/day in group 2. The primary endpoint was change in systolic daytime ambulatory blood pressure at week 12.At week 12, the mean between-group difference in daytime ambulatory blood pressure was 10/4 mmHg (95% confidence interval: 7-14/2-7; P < 0.001/P = 0.0014) in favour of the group 1. The blood pressure goal (daytime ambulatory blood pressure <135/85 mmHg) was achieved in 58% in the group 1 and 20% in the group 2 (P < 0.0001). Discontinuation for drug-related adverse events was low (group 1, n = 7; group 2, n = 6).In patients with resistant hypertension, sequential nephron blockade induces a large and well tolerated reduction in blood pressure via a progressive increase in sodium depletion, and is more effective than sequential renin-angiotensin system blockade.
- Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker. [Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Hypertension 2012 Jun; 59(6):1204-11.
To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex-specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P<10(-4) in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ(2) 1-sided P=0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4, P=8.98 × 10(-7)), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83, P=7.10 × 10(-3)), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4, P=1.52 × 10(-2)). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.
- Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway. [Journal Article, Research Support, Non-U.S. Gov't]
- Pflugers Arch 2012 Jun; 463(6):853-63.
We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin-angiotensin-aldosterone system.